A Safety and Pharmacokinetics Trial of VO659 in SCA1, SCA3 and HD

Main Inclusion Criteria:

• Provide written informed consent (signed and dated). Patients should be assessed fortheir ability to give informed consent using the Evaluation to Sign Consent tool.
• Is ≥25 and ≤60 years of age inclusive, of any gender, at the time of signing theinformed consent.
• Have SCA1, SCA3 or HD meeting one of the following criteria:

1. SCA1 and SCA3: mild to moderate disease with a Scale for Assessment and Rating ofAtaxia (SARA) score of ≥3 and ≤18
2. HD: early manifest, Stage I disease with a Total Functional Capacity (TFC) Scoreof ≥11 and ≤13 and a Unified Huntington's Disease Rating Scale (UHDRS) DiagnosticConfidence Level (DCL) of 4.

• Have genetically confirmed disease, defined by increased cytosine, adenine, andguanine (CAG) repeat length in the disease-causing allele by direct DNA testing. Foreach indication the requirements are:

1. SCA1: ≥41 contiguous, uninterrupted CAG repeats in the ATXN1 gene
2. SCA3: ≥61 repeats in the ATXN3 gene
3. HD: ≥36 CAG repeats in the HTT gene.

• Please note there will be additional inclusion criteria

Main Exclusion Criteria:

• Have any condition that would prevent participation in trial assessments.
• Have one or more pathogenic mutation(s) in another polyQ disease gene, i.e., ATXN2,CACNA1A, ATXN7, TBP, AR, and ATN1, plus either ATXN3 and HTT (for patients with SCA1),ATXN1 and HTT (for participants with SCA3), or ATXN1 and ATXN3 (for participants withHD), in addition to the disease-causing mutation in the ATXN1 (patients with SCA1),ATXN3 (patients with SCA3) or HTT (patients with HD) gene.
• Have clinical diagnosis of moderate or severe chronic migraines or history of thepost-lumbar-puncture headache of moderate or severe intensity requiringhospitalisation or blood patch.
• Have a brain, spinal or systemic disorder that would interfere with the LP process,CSF circulation, or safety assessments.
• Have history of bleeding diathesis or coagulopathy, platelet count less than the lowerlimit of normal unless stable and assessed by the investigator and the Medical Monitorto be not clinically significant.
• Have uncompensated cardiovascular disorder, any past or present cardiac arrhythmia,QTcF values on screening ECG of >470 ms, familial history of long QT syndrome orsudden unexpected death.
• Have a history of attempted suicide, suicidal ideation with a plan that requiredhospital admission and/or change in level of care within 12 months prior to screening.
• Have medical, psychiatric, or other conditions that, in the judgement of theinvestigator, may compromise the patient's ability to understand the patientinformation sheet, to give informed consent, to comply with all trial requirements, orto complete the trial.
• Prior treatment with an antisense oligonucleotide (including siRNA).
• Pregnant or breast-feeding (lactating) women or women who plan to become pregnant orbreast-feed during the trial.
• Unable to undergo and tolerate MRI scans.
• Please note there will be additional exclusion criteria